CA2037004A1 - Preparation of 5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonaniilides - Google Patents
Preparation of 5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonaniilidesInfo
- Publication number
- CA2037004A1 CA2037004A1 CA002037004A CA2037004A CA2037004A1 CA 2037004 A1 CA2037004 A1 CA 2037004A1 CA 002037004 A CA002037004 A CA 002037004A CA 2037004 A CA2037004 A CA 2037004A CA 2037004 A1 CA2037004 A1 CA 2037004A1
- Authority
- CA
- Canada
- Prior art keywords
- triazolo
- aryl
- pyrimidine
- dihydroxy
- triazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
ABSTRACT
5,7-Dihydroxy-N-(aryl)-1,2,4-triazolo[1,5--a]pyrimidine-2-sulfonamides are prepared by the cyclization of N-(3-(((aryl)amino)sulfonyl)-1H-1.2,4--triazol-5-yl)amines with malonyl halides under acidic conditions. With the addition of a phosphorus oxyhalide, malonic acid can be used in place of the malonyl halides and the 5,7-dihydroxy-1,2,4--triazolo[1,5-a]pyrimidine can be directly converted to the corresponding 5,7-dihalo derivative.
5,7-Dihydroxy-N-(aryl)-1,2,4-triazolo[1,5--a]pyrimidine-2-sulfonamides are prepared by the cyclization of N-(3-(((aryl)amino)sulfonyl)-1H-1.2,4--triazol-5-yl)amines with malonyl halides under acidic conditions. With the addition of a phosphorus oxyhalide, malonic acid can be used in place of the malonyl halides and the 5,7-dihydroxy-1,2,4--triazolo[1,5-a]pyrimidine can be directly converted to the corresponding 5,7-dihalo derivative.
Description
~ ~ 3 ~
I
PREPARATION OF 5,7-DIHYDROXY-1.2.4-TRIAZOLO[1,5-a]-~ he pre~ent invention concerns a proces~ for the preparation of 5,7-dihydroxy-N-(aryl)-1,2,4--triazolo[1,5-a]pyrimidine-2-sulfonamides by the cyclization of N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4--triazol-5-yl)amineq with malonyl halides. With the addition of a phosphorus oxyhalide, malonic acid can be used in place of the malonyl halides and the 5,7--dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfon-anilide can be directly converted to the corresponding 5,7-dihalo analog.
Substituted 1,2,4-triazolo[1,5-alpyrimidine-2--sulfonanilides (I) Il N - N J~
Ar- NH-S~/ ~ ~ (I) Il N N A
are valuable herbicides for the selective control of ~eeds in agronomic crops. Among the more valuable 8,147-F -1-2 ~ 3 ~
herbicides o~ formula (I) are those described in U.S.
Patent 4,818,273 in which the substituents A are both either halo, hydroxy or alkoxy. Compounds of this family have generally been prepared via the intermediacy of the 5,7-dihydroxy compounds. For example, the dihydroxy compounds can be halogenated to the 5,7-dihalo analogs, which in turn can be reacted with alkoxides to provide the corresponding 5,7-dialkoxy compounds.
1 C OH hal Oalk \N J~ ~ \N J~ \N J~
()/~ N OH ~))~ N 1 hal ())~ N lOalk The 5,7-dihydroxy compounds have been disclosed a~ being prepared by the cyclization of N-(3-(((aryl)-amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amines (II) with dialkyl malonates in the presence of sodium alkoxide in alcohol followed by acidification of the intermediate trisodium salt (III).
3o ~8,147-r -2--2037~13~
Ar- NH -5 ~ ~ IV~ NaOalklalkOH
l N NH2 alkO alk (I I) OeNa~3 1I N - N J~ H~
Ar - N--S ~</ I
Na~3 0 N N ~ ~OeNae (III) Ar- NH 11 ~/ N~ + Ar- NH-~ OH
11 N 1~ N OH O N NH2 (IV) (V) This process haq the following disadvantageq:
1) the reaction time for the cyclization is generally 24 to 48 hours (hr);
2) the process requires 3 equivalentq of expenqive qodium alkoxide base;
I
PREPARATION OF 5,7-DIHYDROXY-1.2.4-TRIAZOLO[1,5-a]-~ he pre~ent invention concerns a proces~ for the preparation of 5,7-dihydroxy-N-(aryl)-1,2,4--triazolo[1,5-a]pyrimidine-2-sulfonamides by the cyclization of N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4--triazol-5-yl)amineq with malonyl halides. With the addition of a phosphorus oxyhalide, malonic acid can be used in place of the malonyl halides and the 5,7--dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfon-anilide can be directly converted to the corresponding 5,7-dihalo analog.
Substituted 1,2,4-triazolo[1,5-alpyrimidine-2--sulfonanilides (I) Il N - N J~
Ar- NH-S~/ ~ ~ (I) Il N N A
are valuable herbicides for the selective control of ~eeds in agronomic crops. Among the more valuable 8,147-F -1-2 ~ 3 ~
herbicides o~ formula (I) are those described in U.S.
Patent 4,818,273 in which the substituents A are both either halo, hydroxy or alkoxy. Compounds of this family have generally been prepared via the intermediacy of the 5,7-dihydroxy compounds. For example, the dihydroxy compounds can be halogenated to the 5,7-dihalo analogs, which in turn can be reacted with alkoxides to provide the corresponding 5,7-dialkoxy compounds.
1 C OH hal Oalk \N J~ ~ \N J~ \N J~
()/~ N OH ~))~ N 1 hal ())~ N lOalk The 5,7-dihydroxy compounds have been disclosed a~ being prepared by the cyclization of N-(3-(((aryl)-amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amines (II) with dialkyl malonates in the presence of sodium alkoxide in alcohol followed by acidification of the intermediate trisodium salt (III).
3o ~8,147-r -2--2037~13~
Ar- NH -5 ~ ~ IV~ NaOalklalkOH
l N NH2 alkO alk (I I) OeNa~3 1I N - N J~ H~
Ar - N--S ~</ I
Na~3 0 N N ~ ~OeNae (III) Ar- NH 11 ~/ N~ + Ar- NH-~ OH
11 N 1~ N OH O N NH2 (IV) (V) This process haq the following disadvantageq:
1) the reaction time for the cyclization is generally 24 to 48 hours (hr);
2) the process requires 3 equivalentq of expenqive qodium alkoxide base;
3) on acidification, the intermediate trisodium salt (III) yields approximately 5 to 25 percent ring-opened product (V) which carl be 38,147-F -3-2~7~
~ost during the isolation of the desired ?roduct (IV); and 4) the neutralization process requires 3 equivalents of acid and generates considerable quantities of waste brine.
In view of the valuable herbicida1 propertie~
of the sulfonamides (I), it is desirable to have a process for the preparation of N-(aryl)-5,7-dihydroxy--1,2,4-triazolo~1,5-a]pyrimidine-2-sulfonamideY which avoids unnecessary yield loss. It is also desirable to have a process that eliminates the sodium alkoxide base, does not generate large amounts of waste brine, and does not require protracted reaction times.
The present invention concern~ a process for the preparation of N-(aryl)-5,7-dihydroxy-1,2,4--triazolo[1,5-a]pyrimidine-2-sulfonamides of the formula:
R X OH
z~ NH~
Y
wherein X represents H, F, Cl, ~r, lower alkyl or lower alkoxy, 3o ~ represents H. F, Cl or Br, 38,147-F -~-, -R represents H, lower alkyl or lower alkoxy, and Z represents H, Cl or Br, characterized by reacting an N-(3-(((aryl)amino)-sulfonyl)-lH-1,2,4-triazol-5-yl)amine of the formula:
R X
; ~ O NH7 wherein X, Y, R and Z are as previously defined.
with a malonyl halide under acidic conditions in a polar aprotic solvent.
By conducting the reaction in the presence of a phosphorus oxyhalide, malonic acid can be substituted ~or the malonyl halide and the 5,7-dihydroxy-1,2,4--triazolo[1,5-a~pyrimidine-2-sulfonanilide can be directly converted to the corresponding 5,7-dihalo analog. Alternatively, the 5,7-dihalo derivative~ can be prepared by subsequent treatment of the cyclization reaction mixture with a phosphorus oxyhalide.
The present invention has the advantage of being able to prepare 5,7-dihydroxy-1,2,4-triazolo-[1,5--a]pyrimidine-2-sulfonanilideq in a one step process without using any base. By avoiding an acidification step, yield losseq are greatly reduced. Similarly, the 8,147-F _5_ 2~3~n~
generation o~ a waste brine is eliminated. And.
finally, ~ subsequent halogenation step can be combined with the cyclization step to simplify the overall ?rocess for preparing the corresponding 5,7-dihalo derivatives.
As used herein~ the terms "lower alkyl" and "lower alkoxy" are meant to designate straight or branched, saturated alkyl or alkoxy groups of from 1 to 4 carbon atoms.
~ here individual members of the halogen family are not specifically listed, the general terms "halogen", "halide", "halo" and "hal", as used herein, are meant to be construed as being limited to chloro and bromo.
Malonyl halides are commercially available starting materials. Because of its lesser expense and more ready availability, malonyl chloride was preferred over the bromide. The malonyl halide wa~ preferably freshly distilled prior to use.
~ he N-(3-(((aryl)amino)sulfonyl)-lH-1,2,4--triazol-5-yl)amines are known compounds and are described in U.S. Patent 4,734,123. Of these starting materials, X and Y are preferably H, F or Cl. Z is preferably H or Br. For R, the preferred "lower alkyl"
and "lower alkoxy" groups are -CH3, -CH2CH3, -OCH3 and -OCH2CH3. The most preferred group is -CH3.
In the cyclization reaction, the N-(3-(((aryl)-amino)sulfonyl)-lH-1.2,4-triazol-5-yl)amine is condensed ~ith the malonyl halide. In principal. one equivalent of each reagent is required; in practice, a slight excess of the malonyl halide is preferred. Generally, 38,147-F -6-2 ~ 3 ~'~J ~
_, _ from 1.0 to 2.0 equivalents of the malonyl halide are employed, while 1.0 to 1.2 equivalents are preferred.
3y conducting the reaction "under acidic condition~" is meant under conditions wherein no salts in which the product comprises the anionic component are formed. In the basic condensations of the prior art, the trisodium salts (III) are formed as reaction intermediates which must be neutralized with acid to provide the desired products (IV). The present invention envisions the avoidance of such salts as intermediates. Since hydrogen halide is a by-product of the in~tant proce~s, the reaction conditions are inherently acidic. Operation in the presence of the acid generated during the course of the reaction is preferred.
The cyclization reacSion is preferabiy carried out in the presence of a dry polar aprotic solvent which is inert to the reaction conditions. Preferred solvents include but are not limited to alkylnitriles, such as, for example, acetonitrile or butyronitrile; ethers, such as, for example, tetrahydrofuran or dioxane; and carboxylic acid esters, such as, for example, ethyl acetate. The solvents are preferably freshly distilled and dried prior to use.
The cyclization reaction with malonyl halide is generally run from room temperature to 100C. preferably from ambient temperature to 50C.
The cyclization reaction is optionally conducted under an inert atmosphere, such as. for example, under a nitrogen or argon blanket. Although conveniently conducted at atmospheric pressure, the 38,147-F -?--2~7~Q,~
reaction is preferably run under a slight positive nitrogen ?ressure of up to 5 psig (135.8 kPa) which helps in keeping out undesirable atmospheric moisture.
n a typical reaction, the N-(3-(((aryl)amino)-sulfonyl)-lH-1.2,4-triazol-5-yl)amine is dissolved in a dry polar aprotic solvent and is stirred with one equivalent of freshly distilled malonyl halide. After completion of the reaction, usually in from 8 to 24 hr, the 5,7-dihydroxy compound can be recovered by conventional technique~, e.g., by filtration, by extraction or by recrystallization.
Optionally, the malonyl halide may be replaced with malonic acid and with the corresponding phosphorus oxyhalide. At least 2 equivalents of phosphoru~
oxyhalide are required for each equivalent of malonic acid. It is often convenient to use a large excess of the phosphorus oxyhalide. By a large excess is meant from 2 up to 10 equivalents and more over that required by the ideal stoichiometry. When a large excess of phosphorus oxyhalide is employed, the polar aprotic organic solvent can be optionally removed, being effectively replaced by the phosphorus oxyhalide. When using malonic acid and the phosphoru~ oxyhalide in place of the malonyl halide, the reaction is preferably conducted between 70 and 90C.
~f the 5,7-dihalo-1,2,4-triazolo[1,5-a]pyrimi-dine-2-sulfonanilides are desired, the 5.7-dihydroxy compounds can be reacted with a sufficient quantity of ?hosphorus oxyhalide to convert the hydroxy groups to nalides. One equivalent of phosphorus oxyhalide is required for each hydroxy group to be replaced. Thus, at least two equivalents of phosphorus oxyhalide are 38.147-F -.3-2~3'~3~
,~
typically employed to convert the 5.7-dihydroxy compounds to their corresponding 5,7-dihalo counter-?arts. It is often most convenient to use a large - excess o~ the phosphorus oxyhalide which can be added concurrently with the malonyl halide prior to cyclization or which can be added to the reaction mixture after cyclization.
In the most preferred embodiment, the 5,7--dihalo-1,2,4-triazolo[1,5-a1pyrimidine-2-sulfonanilides are prepared directly from the N-(3-(((aryl)amino)-sulfonyl)-lH-1,2.4-triazol-5-yl)amine~ by conducting the cyclization and halogenation reactions consecutively by using at least one equivalent of malonic acid and at least 4 equivalents of phosphorus oxyhalide concurrently. Stoichiometric excesse~ of both reagents are often beneficially employed. The reaction is preferably conducted between 70 and 100C.
In some cases, it is helpful to employ a tertiary amine, such as, for example, dimethyl aniline, ~s a catalyst for the reaction. In those case~ where the uqe of the catalyst is benePicial, the tertiary amine is generally employed at levels in the range of 0.1 to 40 mole percent of the N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine starting material, more preferably in the range of 1 to 20 mole percent.
In a typical reaction, the N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine, one equivalent of malonic acid and a large excess of phosphorus oxyhalide are heated with stirring. After the reaction is complete, the 5,7-dihalo compound can be recovered by conventional techniques. For example, the reaction mixture can be cooled and carefully diluted with water, 38.147-F -9-203~1 o~L~
and the product can be isolated by ~iltration, by extraction or the like.
The r'ollowing example~3 are presented to illustrate the invention and should not be construed as 5 limiting the scope of the invention. All melting points are uncorrected.
Example l Preparation of 5,7-Dihydroxy-N-(2,6--dichloro-3-methylphenyl)-1,2,4--triazolo[1,5-a]pyrimidine-2-sulfonamide CH Cl h3~ 11 N _ N/ + o o CH CN
\=~ o N NH2 Cl Cl CH3 Cl OH
~ 11 N - N ~
To a stirred solution of 2.52 gram~3 (g) (0.0078 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)-amino)sulfonyl)-1H-1.2,4-triazol-5-yl)amine in 100 milliliters (mL) of dry acetonitrile under nitrogen was added 1.5 g (0.01 mole~) of freshly distilled malonyl chloride. The mixture wa~ stirred at ambient temperature overnight (14 hr) and a yellow precipitate formed. The solid product was collected by filtration and dried; mp 280-282C (decompose~). The filtrate wa~
found to contain additional product which was recovered 38,147-F -lO-2~3~
j 1 by concentrating the filtrate to dryness. The combined yield of product was 2.58 g (85 percent yield).
Example 2 ~reparation of 5,7-Dichloro-N-(4-bromo-3--meShylphenyl)-1,2,4-triazolo[1,5-a]pyri-midine-2-sulfonamide 0 Br~\\ NH 11 ~/ N+ POCI
I l N NHz H~ OH
CH3 Cl Br- ~ _ NH-~
Il N N Cl A 3-necked fla~k equipped with a mechanical stirrer and a reflux condenser waA charged with 6.62 g (0.02 moles) of N-(3-(((4-bromo-3-methylphenyl)amino)-sulfonyl)-lH-1,2,4-triazol-5-yl)amine, 2.08 g (0.02 moles) of malonic acid and 20 mL (0.21 mole~) of phosphorus oxychloride. The mixture wa~ stirred and heated in an oil bath at 90C for 24 hr. The mixture wa~ allowed to cool and wa~ poured into ice-water. The resulting solid product wa~ collected by filtration and dried to give 8.4 g (96 percent yield) of light brown solid having an estimated purity of about 85 to 88 percent. Approximately 7 g of the product was slurried in 50 mL of hot o-dichlorobenzene and residual solidq were removed by filtration. Upon cooling, the filtrate 38,147-F
2 ~
'2 ?rovided 5.2 g of product as an orange solid; mp 232-234C (decomposeq).
~xample 3 ~reparation of 5,7-Dichloro-N-(2,6-di-chloro-3-methylphenyl)-1.2,4-triazolo[1,5--a~pyrimidine-2-sulfonamide CH Cl N ~ N~ H
CH3 Cl Otl <~ NH -5 ~ J~ PO~I~
\='~ 11 N :~ N OH
CH Cl Cl (~ NH-C
To a stirred solution of 6.44 g (0.02 moles) of N-(3-(((2.6-dichloro-3-methylphenyl~amino)sulfonyl)-1H--1,2,4-triazol-5-yl)amine in 100 mL of dry acetonitrile was added 2.82 g (0.02 moles) of freshly distilled malonyl chloride. The mixture was stirred at room temperature overnight after which time some starting ~aterial remained. Additional malonyl chloride (0.56 g) was added and stirring was continued for 4 hrs. The reaction mixture was concentrated to dryness and the 38,147-F -12-2~37~
residue was slurried with POC13 (122 g; 0.8 moles) and heated at 90C for 9 hrs. The reaction mixture waq cooled and concentrated under reduced pressure and the residue was poured into ice-water. The resulting ?recipitate was filtered and criea to give 8.35 g of product having a purity of 75 percent (73 percent yield).
Example 4 Preparation of 5,7-Dichloro-N-(3-methyl-phenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2--sulPonamide CH
\ ~ O H
~_ I N - N/ POCI3 2~ ~ 11 N ~ N lCI
A mixture of 19.9 g (0.075 moles) of N-(3-(((3--methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)-amine, 7.9 g (0.075 moles) of malonic acid and 115 g of phosphoruq oxychloride were stirred at 60 to 70C for 15 hr. HPLC analysi~ indicated only 55 percent conver~ion 3 to the desired product. An additional 0.5 g of malonic acid, 20 g of POC13 and 0.5 g of dimethylaniline as a catalyst were added, and stirring and heating were continued until the reaction was complete. About 50 mL
OI' o-xylene were added as a chaser and approximately 115 g of POC13 were recovered by distillation at 70 to 80C
38,147-F _13_ ~37a~
' F~s X
,~ ~ NH -S
o wherein X, Y, R and Z are as previously defined, . with a malonyl halide under acidic canditions in a polari aprotic solvent.
2. The process of Claim 1 in which X and Y are H, F7 or Cl, Z is H or Br, and R is CH3.
~ 3. The process o~ Claim 1 or Z in which the : polar aprotic solvent is an alkylnitrile, an ether or a carboxylic acicl ester.
~ ~ .
j 4. The process o~ any one of the preceding claims in which the temperature i9 maintained between ambient temperature and 100C.
5. The process of any one of the preceding claims which is characterized by the additional step o~
converting the N-aryl 5,7-dihydroxy-1,2,4-triazolo-[1,5--a]pyrimidine-2-sulfonamide to the corresponding 5,7--dihalo compound by directly reacting the reaction mixture with a phosphorus oxyhalideO
; 6. A process ~or the preparation o~ an N--(aryl)-5,7-dihalo-1,2,4 triazolo[l,5-a]pyrimidine-2-sulfonamide of the ~ormula 38,147-F -16-
~ost during the isolation of the desired ?roduct (IV); and 4) the neutralization process requires 3 equivalents of acid and generates considerable quantities of waste brine.
In view of the valuable herbicida1 propertie~
of the sulfonamides (I), it is desirable to have a process for the preparation of N-(aryl)-5,7-dihydroxy--1,2,4-triazolo~1,5-a]pyrimidine-2-sulfonamideY which avoids unnecessary yield loss. It is also desirable to have a process that eliminates the sodium alkoxide base, does not generate large amounts of waste brine, and does not require protracted reaction times.
The present invention concern~ a process for the preparation of N-(aryl)-5,7-dihydroxy-1,2,4--triazolo[1,5-a]pyrimidine-2-sulfonamides of the formula:
R X OH
z~ NH~
Y
wherein X represents H, F, Cl, ~r, lower alkyl or lower alkoxy, 3o ~ represents H. F, Cl or Br, 38,147-F -~-, -R represents H, lower alkyl or lower alkoxy, and Z represents H, Cl or Br, characterized by reacting an N-(3-(((aryl)amino)-sulfonyl)-lH-1,2,4-triazol-5-yl)amine of the formula:
R X
; ~ O NH7 wherein X, Y, R and Z are as previously defined.
with a malonyl halide under acidic conditions in a polar aprotic solvent.
By conducting the reaction in the presence of a phosphorus oxyhalide, malonic acid can be substituted ~or the malonyl halide and the 5,7-dihydroxy-1,2,4--triazolo[1,5-a~pyrimidine-2-sulfonanilide can be directly converted to the corresponding 5,7-dihalo analog. Alternatively, the 5,7-dihalo derivative~ can be prepared by subsequent treatment of the cyclization reaction mixture with a phosphorus oxyhalide.
The present invention has the advantage of being able to prepare 5,7-dihydroxy-1,2,4-triazolo-[1,5--a]pyrimidine-2-sulfonanilideq in a one step process without using any base. By avoiding an acidification step, yield losseq are greatly reduced. Similarly, the 8,147-F _5_ 2~3~n~
generation o~ a waste brine is eliminated. And.
finally, ~ subsequent halogenation step can be combined with the cyclization step to simplify the overall ?rocess for preparing the corresponding 5,7-dihalo derivatives.
As used herein~ the terms "lower alkyl" and "lower alkoxy" are meant to designate straight or branched, saturated alkyl or alkoxy groups of from 1 to 4 carbon atoms.
~ here individual members of the halogen family are not specifically listed, the general terms "halogen", "halide", "halo" and "hal", as used herein, are meant to be construed as being limited to chloro and bromo.
Malonyl halides are commercially available starting materials. Because of its lesser expense and more ready availability, malonyl chloride was preferred over the bromide. The malonyl halide wa~ preferably freshly distilled prior to use.
~ he N-(3-(((aryl)amino)sulfonyl)-lH-1,2,4--triazol-5-yl)amines are known compounds and are described in U.S. Patent 4,734,123. Of these starting materials, X and Y are preferably H, F or Cl. Z is preferably H or Br. For R, the preferred "lower alkyl"
and "lower alkoxy" groups are -CH3, -CH2CH3, -OCH3 and -OCH2CH3. The most preferred group is -CH3.
In the cyclization reaction, the N-(3-(((aryl)-amino)sulfonyl)-lH-1.2,4-triazol-5-yl)amine is condensed ~ith the malonyl halide. In principal. one equivalent of each reagent is required; in practice, a slight excess of the malonyl halide is preferred. Generally, 38,147-F -6-2 ~ 3 ~'~J ~
_, _ from 1.0 to 2.0 equivalents of the malonyl halide are employed, while 1.0 to 1.2 equivalents are preferred.
3y conducting the reaction "under acidic condition~" is meant under conditions wherein no salts in which the product comprises the anionic component are formed. In the basic condensations of the prior art, the trisodium salts (III) are formed as reaction intermediates which must be neutralized with acid to provide the desired products (IV). The present invention envisions the avoidance of such salts as intermediates. Since hydrogen halide is a by-product of the in~tant proce~s, the reaction conditions are inherently acidic. Operation in the presence of the acid generated during the course of the reaction is preferred.
The cyclization reacSion is preferabiy carried out in the presence of a dry polar aprotic solvent which is inert to the reaction conditions. Preferred solvents include but are not limited to alkylnitriles, such as, for example, acetonitrile or butyronitrile; ethers, such as, for example, tetrahydrofuran or dioxane; and carboxylic acid esters, such as, for example, ethyl acetate. The solvents are preferably freshly distilled and dried prior to use.
The cyclization reaction with malonyl halide is generally run from room temperature to 100C. preferably from ambient temperature to 50C.
The cyclization reaction is optionally conducted under an inert atmosphere, such as. for example, under a nitrogen or argon blanket. Although conveniently conducted at atmospheric pressure, the 38,147-F -?--2~7~Q,~
reaction is preferably run under a slight positive nitrogen ?ressure of up to 5 psig (135.8 kPa) which helps in keeping out undesirable atmospheric moisture.
n a typical reaction, the N-(3-(((aryl)amino)-sulfonyl)-lH-1.2,4-triazol-5-yl)amine is dissolved in a dry polar aprotic solvent and is stirred with one equivalent of freshly distilled malonyl halide. After completion of the reaction, usually in from 8 to 24 hr, the 5,7-dihydroxy compound can be recovered by conventional technique~, e.g., by filtration, by extraction or by recrystallization.
Optionally, the malonyl halide may be replaced with malonic acid and with the corresponding phosphorus oxyhalide. At least 2 equivalents of phosphoru~
oxyhalide are required for each equivalent of malonic acid. It is often convenient to use a large excess of the phosphorus oxyhalide. By a large excess is meant from 2 up to 10 equivalents and more over that required by the ideal stoichiometry. When a large excess of phosphorus oxyhalide is employed, the polar aprotic organic solvent can be optionally removed, being effectively replaced by the phosphorus oxyhalide. When using malonic acid and the phosphoru~ oxyhalide in place of the malonyl halide, the reaction is preferably conducted between 70 and 90C.
~f the 5,7-dihalo-1,2,4-triazolo[1,5-a]pyrimi-dine-2-sulfonanilides are desired, the 5.7-dihydroxy compounds can be reacted with a sufficient quantity of ?hosphorus oxyhalide to convert the hydroxy groups to nalides. One equivalent of phosphorus oxyhalide is required for each hydroxy group to be replaced. Thus, at least two equivalents of phosphorus oxyhalide are 38.147-F -.3-2~3'~3~
,~
typically employed to convert the 5.7-dihydroxy compounds to their corresponding 5,7-dihalo counter-?arts. It is often most convenient to use a large - excess o~ the phosphorus oxyhalide which can be added concurrently with the malonyl halide prior to cyclization or which can be added to the reaction mixture after cyclization.
In the most preferred embodiment, the 5,7--dihalo-1,2,4-triazolo[1,5-a1pyrimidine-2-sulfonanilides are prepared directly from the N-(3-(((aryl)amino)-sulfonyl)-lH-1,2.4-triazol-5-yl)amine~ by conducting the cyclization and halogenation reactions consecutively by using at least one equivalent of malonic acid and at least 4 equivalents of phosphorus oxyhalide concurrently. Stoichiometric excesse~ of both reagents are often beneficially employed. The reaction is preferably conducted between 70 and 100C.
In some cases, it is helpful to employ a tertiary amine, such as, for example, dimethyl aniline, ~s a catalyst for the reaction. In those case~ where the uqe of the catalyst is benePicial, the tertiary amine is generally employed at levels in the range of 0.1 to 40 mole percent of the N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine starting material, more preferably in the range of 1 to 20 mole percent.
In a typical reaction, the N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine, one equivalent of malonic acid and a large excess of phosphorus oxyhalide are heated with stirring. After the reaction is complete, the 5,7-dihalo compound can be recovered by conventional techniques. For example, the reaction mixture can be cooled and carefully diluted with water, 38.147-F -9-203~1 o~L~
and the product can be isolated by ~iltration, by extraction or the like.
The r'ollowing example~3 are presented to illustrate the invention and should not be construed as 5 limiting the scope of the invention. All melting points are uncorrected.
Example l Preparation of 5,7-Dihydroxy-N-(2,6--dichloro-3-methylphenyl)-1,2,4--triazolo[1,5-a]pyrimidine-2-sulfonamide CH Cl h3~ 11 N _ N/ + o o CH CN
\=~ o N NH2 Cl Cl CH3 Cl OH
~ 11 N - N ~
To a stirred solution of 2.52 gram~3 (g) (0.0078 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)-amino)sulfonyl)-1H-1.2,4-triazol-5-yl)amine in 100 milliliters (mL) of dry acetonitrile under nitrogen was added 1.5 g (0.01 mole~) of freshly distilled malonyl chloride. The mixture wa~ stirred at ambient temperature overnight (14 hr) and a yellow precipitate formed. The solid product was collected by filtration and dried; mp 280-282C (decompose~). The filtrate wa~
found to contain additional product which was recovered 38,147-F -lO-2~3~
j 1 by concentrating the filtrate to dryness. The combined yield of product was 2.58 g (85 percent yield).
Example 2 ~reparation of 5,7-Dichloro-N-(4-bromo-3--meShylphenyl)-1,2,4-triazolo[1,5-a]pyri-midine-2-sulfonamide 0 Br~\\ NH 11 ~/ N+ POCI
I l N NHz H~ OH
CH3 Cl Br- ~ _ NH-~
Il N N Cl A 3-necked fla~k equipped with a mechanical stirrer and a reflux condenser waA charged with 6.62 g (0.02 moles) of N-(3-(((4-bromo-3-methylphenyl)amino)-sulfonyl)-lH-1,2,4-triazol-5-yl)amine, 2.08 g (0.02 moles) of malonic acid and 20 mL (0.21 mole~) of phosphorus oxychloride. The mixture wa~ stirred and heated in an oil bath at 90C for 24 hr. The mixture wa~ allowed to cool and wa~ poured into ice-water. The resulting solid product wa~ collected by filtration and dried to give 8.4 g (96 percent yield) of light brown solid having an estimated purity of about 85 to 88 percent. Approximately 7 g of the product was slurried in 50 mL of hot o-dichlorobenzene and residual solidq were removed by filtration. Upon cooling, the filtrate 38,147-F
2 ~
'2 ?rovided 5.2 g of product as an orange solid; mp 232-234C (decomposeq).
~xample 3 ~reparation of 5,7-Dichloro-N-(2,6-di-chloro-3-methylphenyl)-1.2,4-triazolo[1,5--a~pyrimidine-2-sulfonamide CH Cl N ~ N~ H
CH3 Cl Otl <~ NH -5 ~ J~ PO~I~
\='~ 11 N :~ N OH
CH Cl Cl (~ NH-C
To a stirred solution of 6.44 g (0.02 moles) of N-(3-(((2.6-dichloro-3-methylphenyl~amino)sulfonyl)-1H--1,2,4-triazol-5-yl)amine in 100 mL of dry acetonitrile was added 2.82 g (0.02 moles) of freshly distilled malonyl chloride. The mixture was stirred at room temperature overnight after which time some starting ~aterial remained. Additional malonyl chloride (0.56 g) was added and stirring was continued for 4 hrs. The reaction mixture was concentrated to dryness and the 38,147-F -12-2~37~
residue was slurried with POC13 (122 g; 0.8 moles) and heated at 90C for 9 hrs. The reaction mixture waq cooled and concentrated under reduced pressure and the residue was poured into ice-water. The resulting ?recipitate was filtered and criea to give 8.35 g of product having a purity of 75 percent (73 percent yield).
Example 4 Preparation of 5,7-Dichloro-N-(3-methyl-phenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2--sulPonamide CH
\ ~ O H
~_ I N - N/ POCI3 2~ ~ 11 N ~ N lCI
A mixture of 19.9 g (0.075 moles) of N-(3-(((3--methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)-amine, 7.9 g (0.075 moles) of malonic acid and 115 g of phosphoruq oxychloride were stirred at 60 to 70C for 15 hr. HPLC analysi~ indicated only 55 percent conver~ion 3 to the desired product. An additional 0.5 g of malonic acid, 20 g of POC13 and 0.5 g of dimethylaniline as a catalyst were added, and stirring and heating were continued until the reaction was complete. About 50 mL
OI' o-xylene were added as a chaser and approximately 115 g of POC13 were recovered by distillation at 70 to 80C
38,147-F _13_ ~37a~
' F~s X
,~ ~ NH -S
o wherein X, Y, R and Z are as previously defined, . with a malonyl halide under acidic canditions in a polari aprotic solvent.
2. The process of Claim 1 in which X and Y are H, F7 or Cl, Z is H or Br, and R is CH3.
~ 3. The process o~ Claim 1 or Z in which the : polar aprotic solvent is an alkylnitrile, an ether or a carboxylic acicl ester.
~ ~ .
j 4. The process o~ any one of the preceding claims in which the temperature i9 maintained between ambient temperature and 100C.
5. The process of any one of the preceding claims which is characterized by the additional step o~
converting the N-aryl 5,7-dihydroxy-1,2,4-triazolo-[1,5--a]pyrimidine-2-sulfonamide to the corresponding 5,7--dihalo compound by directly reacting the reaction mixture with a phosphorus oxyhalideO
; 6. A process ~or the preparation o~ an N--(aryl)-5,7-dihalo-1,2,4 triazolo[l,5-a]pyrimidine-2-sulfonamide of the ~ormula 38,147-F -16-
Claims (10)
1. 1. A process for the preparation of an N--(aryl)-5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2--sulfonamide of the formula wherein X represents H, F, Cl, Br, lower alkyl or lower alkoxy, Y represents H, F, Cl or Br, R represents H, lower alkyl or lower alkoxy, and Z represents H, Cl or Br, characterized by reacting an N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine of the formula:
wherein X, Y, R and Z are as previously defined, with a malonyl halide under acidic conditions in a polar aprotic solvent.
wherein X, Y, R and Z are as previously defined, with a malonyl halide under acidic conditions in a polar aprotic solvent.
2. The process of Claim 1 in which X and Y are H, F, or Cl, Z is H or Br, and R is CH3.
3. The process of Claim 1 or 2 in which the polar aprotic solvent is an alkylnitrile, an ether or a carboxylic acid ester.
4. The process of any one of the preceding claims in which the temperature is maintained between ambient temperature and 100°C.
5. The process of any one of the preceding claims which is characterized by the additional step of converting the N-aryl-5,7-dihydroxy-1,2,4-triazolo-[1,5--a]pyrimidine-2-sulfonamide to the corresponding 5,7--dihalo compound by directly reacting the reaction mixture with a phosphorus oxyhalide.
6. A process for the preparation of an N--(aryl)-5,7-dihalo-1,2,4-triazolo[1,5-a]pyrimidine-2--sulfonamide of the formula 38,147-F -16- wherein A represents Cl or Br, X represents H, F, Cl, Br or lower alkyl, Y represents H, F, Cl or Br, R represents H, lower alkyl or lower alkoxy, and Z represents H, Cl or Br, characterized by reacting an N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine of the formula:
wherein X. Y, R and Z are as previously defined, with at least one equivalent of malonic acid and at least 4 equivalents of a phosphorus oxyhalide under acidic conditions.
38,147-F -17-
wherein X. Y, R and Z are as previously defined, with at least one equivalent of malonic acid and at least 4 equivalents of a phosphorus oxyhalide under acidic conditions.
38,147-F -17-
7. The process of Claim 6 in which A is Cl and the phosphorus oxyhalide is POCl3.
8. The process of Claim 6 or 7 in which X and Y are H, F or Cl, Z is H or Br, and R is CH3.
9. The process of Claim 7 in which POCl3 in excess is used as the solvent.
10. The process of any one of Claims 6-9 in which the temperature is maintained between 70 and 100°C .
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/484,960 US5006656A (en) | 1990-02-26 | 1990-02-26 | Preparation of 5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonanilides |
| US484,960 | 1990-02-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2037004A1 true CA2037004A1 (en) | 1991-08-27 |
Family
ID=23926349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002037004A Abandoned CA2037004A1 (en) | 1990-02-26 | 1991-02-25 | Preparation of 5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonaniilides |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5006656A (en) |
| EP (1) | EP0444747B1 (en) |
| JP (1) | JP2992099B2 (en) |
| KR (1) | KR0172965B1 (en) |
| CN (1) | CN1034121C (en) |
| AT (1) | ATE138066T1 (en) |
| AU (1) | AU625020B2 (en) |
| CA (1) | CA2037004A1 (en) |
| DE (1) | DE69119450T2 (en) |
| DK (1) | DK0444747T3 (en) |
| ES (1) | ES2087229T3 (en) |
| HU (1) | HU206706B (en) |
| IL (1) | IL97355A (en) |
| NZ (1) | NZ237210A (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0724586B1 (en) * | 1993-10-18 | 2002-01-23 | Dow AgroSciences LLC | Process for preparing n-(2,6-dichloro-3-methylphenyl)-5-7-dihalo[1,2,4]triazolo[1,5a]pyrimidine-2-sulfonamide by cyclization and halo-dehydroxylation |
| RU2147584C1 (en) * | 1995-10-27 | 2000-04-20 | Американ Цианамид Компани | Method of synthesis of dihaloidazolopyrimidines and method of synthesis of dihydroxyazolopyrimidines |
| US6376424B1 (en) | 1998-01-21 | 2002-04-23 | Syngenta Crop Protection, Inc. | Herbicidal composition |
| DE69912936T2 (en) * | 1998-01-26 | 2004-04-22 | Dow Agrosciences Llc, Indianapolis | PRODUCTION OF N-ARYLSULFONAMIDE COMPOUNDS |
| SA05260065B1 (en) | 2004-03-26 | 2009-12-29 | سينجنتا بارتيسيبيشنزا ايه جى | A Herbicidal Combination |
| CN103254195B (en) * | 2013-03-26 | 2016-08-03 | 内蒙古医科大学 | 7-amino-tetrazole [1,5-a] pyrimidine-5-alcohol (compound II) and synthetic route thereof |
| CN103204855A (en) * | 2013-03-26 | 2013-07-17 | 内蒙古医科大学 | Compound I tetrazole (1, 5-a) pyrimidine-5, 7-diol and synthetic route thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19775042I2 (en) * | 1983-11-14 | 2001-05-03 | Dowelanco | 1, 2, 4-triazolo 1, 4-a pyrimidine-2-sulfonamides and preparations and method for combating unwanted plants and the nitration of ammonium nitrogen in the soil |
| US4818273A (en) * | 1983-11-14 | 1989-04-04 | The Dow Chemical Company | Substituted 1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamides, compositions containing them, and their utility as herbicides |
| US4822404A (en) * | 1984-01-26 | 1989-04-18 | The Dow Chemical Company | Sulfonamides derived from substituted 2-amino-1,2,4-triazolo (1,5-a) pyrimidines and compositions and methods of controlling undesired vegetation |
| US4734123A (en) * | 1986-05-06 | 1988-03-29 | The Dow Chemical Company | Novel sulfonamides and method of making |
| DD255735A1 (en) * | 1986-11-03 | 1988-04-13 | Hydrierwerk Rodleben Veb | PROCESS FOR THE PREPARATION OF 5-METHYL-7-HALOGEN-6-NITRO-1,2,4-TRIAZOLO- (1,5-A) PYRIMIDINES |
| US4904301A (en) * | 1988-04-19 | 1990-02-27 | The Dow Chemical Company | 5-Fluoromethyl-1,2,4-triazolo(1,5-A)-pyrimidines |
| AU6580090A (en) * | 1990-11-02 | 1992-04-30 | Mitsui Chemicals, Inc. | Polyol and utilization thereof |
-
1990
- 1990-02-26 US US07/484,960 patent/US5006656A/en not_active Expired - Fee Related
-
1991
- 1991-02-25 EP EP91200395A patent/EP0444747B1/en not_active Expired - Lifetime
- 1991-02-25 HU HU91623A patent/HU206706B/en not_active IP Right Cessation
- 1991-02-25 DK DK91200395.1T patent/DK0444747T3/en active
- 1991-02-25 NZ NZ237210A patent/NZ237210A/en unknown
- 1991-02-25 AT AT91200395T patent/ATE138066T1/en not_active IP Right Cessation
- 1991-02-25 CA CA002037004A patent/CA2037004A1/en not_active Abandoned
- 1991-02-25 ES ES91200395T patent/ES2087229T3/en not_active Expired - Lifetime
- 1991-02-25 AU AU71353/91A patent/AU625020B2/en not_active Ceased
- 1991-02-25 IL IL9735591A patent/IL97355A/en unknown
- 1991-02-25 CN CN91101104A patent/CN1034121C/en not_active Expired - Fee Related
- 1991-02-25 DE DE69119450T patent/DE69119450T2/en not_active Expired - Fee Related
- 1991-02-25 KR KR1019910003033A patent/KR0172965B1/en not_active IP Right Cessation
- 1991-02-26 JP JP3030943A patent/JP2992099B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| KR0172965B1 (en) | 1999-02-01 |
| IL97355A0 (en) | 1992-05-25 |
| DK0444747T3 (en) | 1996-06-03 |
| JP2992099B2 (en) | 1999-12-20 |
| IL97355A (en) | 1995-01-24 |
| DE69119450T2 (en) | 1996-09-26 |
| HUT58725A (en) | 1992-03-30 |
| HU206706B (en) | 1992-12-28 |
| JPH0559057A (en) | 1993-03-09 |
| KR910021403A (en) | 1991-12-20 |
| US5006656A (en) | 1991-04-09 |
| NZ237210A (en) | 1992-12-23 |
| ES2087229T3 (en) | 1996-07-16 |
| CN1034121C (en) | 1997-02-26 |
| HU910623D0 (en) | 1991-09-30 |
| AU625020B2 (en) | 1992-06-25 |
| DE69119450D1 (en) | 1996-06-20 |
| EP0444747A2 (en) | 1991-09-04 |
| EP0444747A3 (en) | 1992-01-29 |
| AU7135391A (en) | 1991-08-29 |
| EP0444747B1 (en) | 1996-05-15 |
| CN1054251A (en) | 1991-09-04 |
| ATE138066T1 (en) | 1996-06-15 |
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